The long-term goal of my laboratory is to elucidate the mechanisms that control mechanotransduction in hair cells, and the defects in this process that cause deafness. We propose here to identify and study proteins that interact with PCDH15 and TMHS/ LHFPL5 (referred to in the following as LHFPL5), two components of the hair cell's mechanotransduction machinery. Based on preliminary data, we hypothesize that PCDH15 and LHFPL5 are components of a larger protein complex that regulates the activity of mechanically gated ion channels in hair cells. We predict that mutations in complex components lead to auditory impairment. To test our hypothesis, we will: (i) Determine the function of LHFPL5 and some of its close homologues for mechano-transduction and auditory perception; (ii) continue our identification of hair cell proteins that interact with PCDH15 and/or LHFPL5; (iii) functionall characterize proteins that interact with PCDH15 and/or LHFPL5; (iv) determine their relevance for auditory impairment in humans. Our preliminary data show the feasibility of our approach. We have already identified hair cell proteins that interact with PCDH15 and LHFPL5, at least one of which is linked to auditory impairment in humans.